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Original Research: COPD |

Pooled Clinical Trial Analysis of Tiotropium Safety* FREE TO VIEW

Steven Kesten, MD, FCCP; Michele Jara, DSc, MPH; Charles Wentworth, MS; Stephan Lanes, PhD
Author and Funding Information

*From Boehringer Ingelheim Pharmaceuticals (Drs. Kesten and Lanes), Ridgefield, CT; Epidemiology Consulting LLC (Dr. Jara), LLC, Danbury, CT; and Analytic Consulting Solutions (Mr. Wentworth), Wakefield, RI.

Correspondence to: Steven Kesten, MD, FCCP, Therapeutic Program Director, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, Ridgefield, CT 06877-0368; e-mail: skesten@rdg.boehringer-ingelheim.com



Chest. 2006;130(6):1695-1703. doi:10.1378/chest.130.6.1695
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Background: Marketing approval of pharmaceutical products is often based on data from several thousand subjects or fewer. Evaluation of safety is greatly enhanced by augmenting the safety database with postapproval studies.

Methods: We conducted a pooled analysis of adverse event data from 19 randomized, double-blind, placebo-controlled trials with tiotropium in patients with obstructive lung disease. We computed incidence rates and rate ratios (RRs) for various reported adverse event end points of interest. Patients contributed person-time to the analysis as long as they were in the study until 30 days after treatment (tiotropium, placebo), or until they had the event of interest, whichever came first. Studies were pooled using the Mantel-Haenszel estimator, and we used 95% confidence intervals (CIs) to assess the precision of effect estimates.

Results: The pooled trial population includes 4,435 tiotropium patients and 3,384 placebo patients contributing 2,159 person-years of exposure to tiotropium and 1,662 person-years of exposure to placebo. Dyspnea, dry mouth, COPD exacerbation, and upper respiratory tract infection were the most commonly reported events. There was a higher relative risk of dry mouth in the tiotropium group (RR, 3.60; 95% CI, 2.56 to 5.05). There was a lower risk of dyspnea (RR, 0.64; 95% CI, 0.50 to 0.81) and COPD exacerbation (RR, 0.72; 95% CI, 0.64 to 0.82) in patients receiving tiotropium compared to patients receiving placebo. Other results of interest are as follows: (1) all-cause mortality (RR, 0.76; 95% CI, 0.50 to 1.16); (2) cardiovascular mortality (RR, 0.57; 95% CI, 0.26 to 1.26); and (3) respiratory mortality (RR, 0.71; 95% CI, 0.29 to 1.74). The relative risk of urinary retention was 10.93 (95% CI, 1.26 to 94.88).

Conclusions: Pooling of adverse event data from preapproval and postapproval tiotropium clinical trials increase the precision of effect estimates and supports the present safety profile of tiotropium.

The ascertainment of product safety in clinical trials is crucial in the development of new chemical entities for the treatment of disease. The organization applying for regulatory approval must demonstrate an acceptable risk/benefit ratio, and adequately describe the safety of the medication. While much of the safety information available at the time of approval can be found in package inserts, through requests to regulatory agencies, or through pharmaceutical company drug information services, further contributions to safety evaluation after approval, especially from clinical trials, are often not readily available to the health-care community in an integrated form. In addition, such information may not be published in medical journals, perhaps related to the perception that this information is less interesting than novel efficacy or bench research data. Nevertheless, the additional information obtained after approval can assist in refining the incidence of expected adverse events and identifying previously unrecognized adverse effects.

Tiotropium is a novel, once-daily inhaled anticholinergic that has its effect through prolonged blockade of the muscarinic M3 receptor and is indicated for the treatment of COPD including chronic bronchitis and emphysema.1Tiotropium, 18 μg qd, has been available for patients since June 2002. Since that time, additional clinical trials28 have been completed that have contributed to a large database. Efficacy data have demonstrated consistent improvements in lung function over 24 h as well as improvements in dyspnea, health-related quality of life, exacerbations, and exercise tolerance. To date, adverse events have been consistent with those expected with an inhaled anticholinergic and with the safety profile of ipratropium bromide.911

The purpose of the present report is to describe the clinical safety of tiotropium using analyses of selected adverse events in an integrated database of placebo-controlled, randomized, double-blind clinical trials. Owing to the virtues of randomization in reducing bias due to confounding, placebo-controlled trials are generally considered to be the most informative means of assessing causal effects of medications. Clinical trials, however, are generally limited in detecting rare effects due to the relatively small number of participants required to test primary efficacy end points. By integrating information across multiple studies in a pooled analysis, the size of the study population is effectively increased, thereby enhancing the precision of effect estimates and improving detection of adverse events. This analysis focuses on selected adverse events including events that might be expected as a result of anticholinergic pharmacology, clinically significant events, and events of public health interest.

Study Population

Inclusion criteria for entry into the pooled safety database were completed clinical trials in the tiotropium HandiHaler (Boehringer Ingelheim International GmbH; Ingelheim, Germany) project database as of May 2004 with the following characteristics: tiotropium (18 μg qd), placebo-controlled, and parallel-group study design. The 18-μg dosage included in the pooled analysis was chosen because of the relatively smaller amount of data for other doses, and to reflect the use of the approved dose of tiotropium.

Nineteen trials of tiotropium met the inclusion criteria (Boehringer Ingelheim trials 205.114, 205.115, 205.116, 205.123, 205.124, 205.127, 205.130, 205.131, 205.137, 205.201, 205.202, 205.214, 205.215, 205.218, 205.223, 205.230, 205.257, 205.266, 205.276). These included studies of tiotropium in patients with COPD and a limited number of trials in patients with asthma. A literature search revealed no published studies that met the aforementioned criteria.

The protocols for all trials in COPD patients were similar. COPD trials sought patients who had a diagnosis of COPD with objective documentation of airflow limitation, were at least 40 years of age, and had a smoking history of at least 10 pack-years. Patients with a history of asthma were excluded in the COPD trials. Excluded by protocol were patients with symptomatic prostatic hypertrophy or bladder neck obstruction, and narrow-angle glaucoma; although more recent protocols have moved the first two disorders to a caution statement. In earlier protocols, patients who were hospitalized for congestive heart failure in the preceding 3 years, had a cardiac arrhythmia requiring drug therapy, or had a myocardial infarction within the past year were excluded. Other than those circumstances, patients with ischemic heart disease or congestive heart failure were not specifically excluded. The cardiac exclusion criteria were liberalized for more recent trials to exclude only patients who were hospitalized for heart failure in the preceding year, had a life-threatening cardiac arrhythmia or an arrhythmia requiring a change in drug therapy within the last year, or a myocardial infarction within the preceding 6 months.

The major differences in protocols between the two parallel-group trials in asthma patients and those in COPD patients, besides the medical indication, were in patient age and smoking status. While the COPD trials allowed entry of current smokers at least 40 years of age, the trials in asthma patients included patients aged 18 through 75 years and excluded current smokers. Except for the requirement for spirometric reversibility in the asthma trials, all other inclusion and exclusion criteria were similar. The protocols for the two trials in asthma patients differed only with regard to the presence of nocturnal asthma as an inclusion criterion for one of the clinical trials.

Protocols were approved by institutional review boards. Written, informed consent was obtained from all patients.

Adverse Event Reporting

Investigators in the clinical trials were required to collect, document, and report to Boehringer Ingelheim all adverse events occurring during the course of the clinical trial (ie, from signing the informed consent onwards). An adverse event is defined as any untoward medical occurrence in a clinical investigation subject administered trial medication (active or placebo) and that does not necessarily have to have a causal relationship with this treatment. A serious adverse event is defined as any adverse event that results in death; is immediately life threatening; results in persistent or significant disability/incapacity; requires or prolongs patient hospitalization; is a congenital anomaly/birth defect; or is to be deemed serious for any other reason representing a significant hazard, which is comparable to the aforementioned criteria. All adverse events, serious and nonserious, were required to be fully documented on the appropriate case report forms. The verbatim terms used by the investigators to report adverse events were classified while the trial remained blinded by Boehringer Ingelheim according to a standard medical coding dictionary (eg, Medical Dictionary for Regulatory Activities), which is the international medical terminology developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.

Selected Events

The Medical Dictionary for Regulatory Activities contains more detail (ie, is more specific) than is needed to accurately classify disease states. Reported adverse events with different codes often describe medically similar events (eg, urinary retention, difficulty urinating), and precision is lost when medically homogeneous terms are analyzed separately. To more accurately assess adverse events, we developed selected events by combining adverse events into medically similar categories. Selected event end points were developed for the following: events possibly related to antimuscarinic effects, events related to the administration of an inhaled product, events that appeared to be imbalanced in the phase III program, and events of public health and regulatory importance, such as myocardial infarction and cardiac arrest. To create the selected event end points, we combined adverse events defined using both the coded preferred term and the verbatim adverse event term noted on a patient’s case report form. This process was conducted in collaboration with a pulmonologist employed by Boehringer Ingelheim after completion and unblinding of the trials, but without knowledge of the patient’s treatment assignment.

Statistical Analysis

Incidence rates of selected events were computed as the number of patients having an event divided by the person-years at risk.12This analysis takes into account duration of exposure, in that patients contribute person-time as long as they were in the study until 30 days after treatment (tiotropium, placebo) or until they had the event of interest, whichever came first. To explore possible heterogeneity between trials prior to pooling, we evaluated trial-specific incidence rate ratios (RRs) of total adverse events (p = 0.05) and serious adverse events (p = 0.16)13 using a fixed-effects model. As tests for homogeneity are not very powerful and large p values do not necessarily indicate the absence of heterogeneity, trial-specific incidence rates and incidence RRs were then visually examined. Any variability noted in estimates by trial was assessed in light of any differences in trial protocol.12 One large trial (Boehringer Ingelheim trial 205.266)8 had low rates of adverse events due to a systematic difference in the trial protocol and was only included in the analysis of serious adverse events. By protocol, this trial collected only serious adverse events except when the investigator determined another nonserious event to be a contributing factor to the serious event being reported.

Finally, as a sensitivity analysis, the analysis was repeated after removing outliers. Analyses are presented separately for selected adverse events, serious adverse events, and fatal adverse events.

To measure the strength of the effect, incidence RRs were computed as the incidence rate in the tiotropium group divided by the incidence rate in the placebo group, using the Mantel-Haenszel RR estimator controlling for study. The stability or precision of each effect estimate is indicated by the width of its 95% confidence interval (CI).12 CIs that include the null value (zero for a difference, or 1.0 for a ratio) imply p values > 0.05; CIs that do not include the null value imply p values < 0.05. Analyses of different events are considered independent from one another, so any patients who have several different kinds of multiple adverse events are included in analyses of each event. People who had multiple occurrences of the same event were included only until the occurrence of the first event. Some results are based on rare events and are often inconclusive. Nevertheless, we have included results that may be clinically relevant because they may suggest either adverse risks or benefits of using tiotropium.

The pooled trial population presents information on 7,819 patients from 19 clinical trials, including 4,435 tiotropium-treated patients and 3,384 placebo-treated patients, contributing 2,159 person-years of exposure to tiotropium and 1,662 person-years of exposure to placebo. The distributions of treatment groups according to demographics baseline disease characteristics and duration of exposure are shown in Table 1 . The study population was balanced between the tiotropium and placebo groups. Most of the patients were white with a mean age of 64 years, and 79% were male. There was no difference between treatment groups in duration of COPD (a mean for tiotropium patients of 10.0 years) and smoking history (mean, 44.8 pack-years). The mean FEV1 percentage of predicted of the population was 43%. There were proportionally fewer patients in the tiotropium group in the two oldest age groups, the placebo group had significantly more nonwhite patients and male patients. The FEV1 (percentage of predicted) appeared to be higher in the tiotropium group.

In the pooled trials, 1,664 patients (38%) received tiotropium 18 μg qd for 90 to 180 days and 2,320 patients (52%) received tiotropium for > 180 days (Table 1). Twenty-four percent of patients receiving placebo discontinued participation prior to the planned end date compared with 16% of patients receiving tiotropium (χ2 = 73.32, p < 0.0001). Of these, 15% of placebo-treated patients compared with 9% of tiotropium-treated patients discontinued due to an adverse event (χ2 = 64.19, p < 0.0001).

Selected Adverse Events

Results from the pooled analysis of placebo-controlled trials are presented in Table 2 for selected adverse events. The subset of selected adverse events that are classified as serious, including fatal adverse events, is presented in Table 3 . Inherently serious cardiac conditions, such as cardiovascular mortality (RR, 0.57; 95% CI, 0.26 to 1.26), cardiac arrest (RR, 0.90; 95% CI, 0.26 to 3.15), and myocardial infarction (RR, 0.74; 95% CI, 0.26 to 2.07) did not occur more frequently among patients receiving tiotropium than patients receiving placebo, although effect estimates for these end points are imprecise. Among heart rate and rhythm disorders, the relative risks of tachycardia (excluding ventricular tachycardia and fibrillation) were 1.68 (95% CI, 0.69 to 4.11) for any tachycardia and 1.16 (95% CI, 0.33 to 4.03) for serious tachycardia. The relative risk of “other” arrhythmias in patients receiving tiotropium compared with patients receiving placebo was 2.71 (95% CI, 1.10 to 6.65). The selected event term, other arrhythmias, used in the pooled analysis is a category containing dysrrhythmias that were not analyzed as separate selected event terms (including such terms as bradycardia, irregular heart beat, and extrasystoles) and does not include ventricular tachycardia/fibrillation or atrial fibrillation. There was no apparent excess of other arrhythmias classified as serious (RR, 0.92; 95% CI, 0.27 to 3.14). The relative risk of left-heart failure among patients receiving tiotropium compared with patients receiving placebo was 0.46 (95% CI, 0.21 to 1.00). There was no increase in total and serious events due to ischemic heart disease.

Among GI disorders, there was a higher risk of dry mouth in patients receiving tiotropium (RR, 3.60; 95% CI, 2.56 to 5.05), none of which was classified as serious. The relative risk of dysphagia was 5.91 (95% CI, 0.60 to 58.31). There was no increased risk of abdominal pain, constipation, dyspepsia, or nausea associated with tiotropium use.

Among metabolism and nutrition disorders, there were five cases of dehydration in the tiotropium group and none in the placebo group (Table 2), which occurred in patients with concomitant illness that may have contributed to the clinical outcome. Computation of RR is not possible given the absence of events in the placebo group. Analysis of serious adverse events (Table 3) shows six patients with dehydration in tiotropium users compared with one patient in the placebo group (RR, 4.64; 95% CI, 0.48 to 45.14). There was no apparent increased risk of diabetes overall (RR, 0.99; 95% CI, 0.41 to 2.37), although the relative risk of hyperglycemic events was 1.69 (95% CI, 0.50 to 5.69).

For renal and urinary disorders, the relative risk of urinary retention in patients receiving tiotropium compared with patients receiving placebo was 10.93 (95% CI, 1.26 to 94.88). Although the relative risk of serious prostatic disorders was 5.32 (95% CI, 0.59 to 48.33), there was no association of tiotropium with prostatic disorders in the analysis of all selected events (RR, 1.04; 95% CI, 0.46 to 2.35).

In the analysis of selected adverse events for infectious respiratory disorders, there was a lower risk of pneumonia among patients receiving tiotropium (RR, 0.64; 95% CI, 0.42 to 0.98). The risk of serious pneumonia was lower (RR, 0.60; 95% CI, 0.41 to 0.87) in patients receiving tiotropium. The relative risk of laryngitis was 2.79 (95% CI, 0.70 to 11.08). The risk of upper respiratory tract infection (URTI) was not associated with tiotropium use (RR, 0.97; 95% CI, 0.84 to 1.13); however, there were three cases of serious URTI in patients receiving tiotropium compared with no cases in patients receiving placebo.

In the analysis of selected adverse events for noninfectious respiratory disorders, there was a lower risk of lower respiratory events including COPD exacerbation (RR, 0.72; 95% CI, 0.64 to 0.82), dyspnea (RR, 0.64; 95% CI, 0.50 to 0.81), and productive cough (RR, 0.49; 95% CI, 0.24 to 0.99) among patients receiving tiotropium compared to patients receiving placebo. The relative risk of bronchospasm was 1.66 (95% CI, 0.65 to 4.24) and was 1.53 (95% CI, 0.78 to 2.99) for epistaxis. The most common serious adverse event was COPD exacerbation. There was a lower incidence of serious COPD exacerbations among tiotropium-treated patients relative to the placebo group (RR, 0.68; 95% CI, 0.54 to 0.85)

For skin disorders, the relative risk of pruritis in tiotropium users was 1.61 (95% CI, 0.68 to 3.82). There was no increased risk of other skin or subcutaneous tissue disorders, including angioedema, rash, and urticaria. There was no increased risk of serious events among these disorders. An analysis of other selected events indicated no increased risk of glaucoma, other visual disturbances, chest pain, edema, fungal infections, musculoskeletal and connective tissue disorders, CNS disorders, or psychiatric disorders.

Fatal Events

For all-cause mortality, the relative risk in patients receiving tiotropium compared with patients receiving placebo was 0.76 (95% CI, 0.50 to 1.16). The relative risk for cardiovascular mortality was 0.57 (95% CI, 0.26 to 1.26) and for respiratory mortality was 0.71 (95% CI, 0.29 to 1.74) [Table 3].

Marketing approval of pharmaceutical products is generally based on review of trials often containing several thousand exposed subjects in controlled trials and concluding that a drug has a favorable risk/benefit profile. The evaluation of safety continues beyond the core registration trials and can include phase IV trials, as well as retrospective studies based on claims databases and spontaneous reporting of adverse events. Tiotropium was initially approved and marketed in several countries in Europe in June 2002 and has since been available in > 70 countries. As of May 2004, a total of 19 placebo-controlled clinical trials28,1420 in patients with obstructive lung disease had been completed. While many of the individual studies have been reported, the combined population provides an opportunity to determine more precise incidences of expected adverse events as well as an opportunity to identify infrequent adverse events. We specifically chose to examine adverse events that are expected based on the pharmacology of anticholinergics, events that are common in COPD (ie, respiratory and cardiac events)21 and events of general public health interest. The pooled trial population included 4,435 tiotropium-treated patients and 3,384 placebo-treated patients that led to a total exposure of 2,159 patient-years to tiotropium and 1,662 patient-years to placebo. The pooled analysis provided findings consistent with expected adverse events related to anticholinergics such as dry mouth, urinary retention, and tachycardia. We also found a decreased risk for COPD exacerbations and dyspnea. Many of the events that appear balanced between groups occur with low frequencies and are still measured imprecisely. Continued addition of further ongoing and planned clinical trials to this database will enhance our ability to more precisely discern rare adverse events.

Inhaled medications with anticholinergic properties have a long history of use. Inhaled pharmaceutical products for the treatment of pulmonary disease have been formally manufactured for regulatory approval and widespread market use for > 20 years. Inhaled medications such as ipratropium bromide and oxitropium have gained widespread acceptance in the treatment of COPD and are considered to be safe and effective products.2223 Common recognized unwanted effects include difficulties in urination, urinary retention, dry mouth, constipation, increase in heart rate, palpitations, and narrow angle glaucoma.910 Other adverse events are described in labeling, but causal mechanisms are uncertain.910 In general, such adverse events are usually included in labeling based on small imbalances in controlled clinical trials or a somewhat subjective interpretation of spontaneous adverse event reports to the pharmaceutical companies or regulatory agencies.

The most common adverse effects noted with tiotropium to date have been dry mouth as well as a higher incidence of events potentially related to mucosal dryness, including epistaxis, hoarseness, laryngitis, and pharyngitis. Less common potentially anticholinergic effects include constipation, urinary retention, urinary tract infection, and tachycardia (such as supraventricular tachyarrhythmia). However, based on the present analysis, the excess risk for these events is imprecise and the CIs were not adjusted for multiple comparisons. Some of the differences between the groups that appear to be significantly different according to the CIs may be spurious due to the multiple tests that have been conducted.

Studies outside of the pharmaceutical industry can provide valuable assistance in the evaluation of safety, although the focus is most often on efficacy. The Lung Health Study24is a 5-year study evaluating 5,887 patients with COPD who were randomized to either a usual-care group or a group who received an active smoking cessation program. The smoking cessation group was further divided into those receiving regular inhaled ipratropium or placebo. In the Lung Health Study, it appeared that there was an increased incidence of serious cardiac events in patients assigned to the ipratropium group.2526 Further analysis based on compliance indicated that there was no association between actual use of ipratropium and cardiac mortality; however, an association with supraventricular arrhythmias was observed.25 The present analysis of tiotropium provides some reassurance that total mortality, including cardiovascular mortality and respiratory mortality, is not elevated among users of tiotropium.

A metaanalysis27 was published evaluating the safety of short-acting and long-acting β-agonists in patients with asthma and COPD. The authors27 concluded that there was an excess risk for adverse cardiovascular events (p < 0.001), the majority of which were sinus tachycardia. The major events included atrial fibrillation, congestive heart failure, syncope, ventricular tachycardia, myocardial infarction, sudden death, and cardiac arrest. The limitations of the metaanalysis related to the accessibility of the safety database within each clinical trial reported, as well as the lack of information on adverse events reported in many trials. The advantage of the present analysis is that all reported safety information was collected in an identical manner in controlled clinical trials and that the entire safety database with complete information was available for analysis.

Clinical trials with positive efficacy outcomes are common in peer-reviewed journals. It is less common to see publication of trials with negative findings or trials presenting comprehensive safety data of pharmaceutical products. This fact makes it difficult to obtain a comprehensive picture of drug safety from published literature. Recent events with drugs such as cyclooxygenase 2 inhibitors and antidepressants suggest the need for increased vigilance on drug safety.2829 The present analysis should encourage others to openly examine safety parameters in approved products and permit open discussion and dissemination of results.

In summary, assessment of adverse events shows tiotropium to be most strongly associated with a reduced risk of COPD exacerbations and dyspnea. The strongest associations for unintended adverse events were for dry mouth and urinary retention. Few of the selected adverse events were classified as serious. The most common serious adverse event was COPD exacerbation, and a lower incidence of COPD exacerbation among tiotropium patients was the largest difference between treatment groups in serious adverse events. Although results for these end points are inconclusive, inherently serious conditions, such as overall mortality, cardiovascular mortality, cardiac arrest, and myocardial infarction, did not occur more frequently among patients receiving tiotropium. Larger numbers of patients will permit analysis of subgroups that may be at increased risk of either adverse events or heightened benefits. The present study demonstrates the value of optimizing approaches to safety for recently approved medications or devices and dissemination of such data.

Abbreviations: CI = confidence interval; RR = risk ratio; URTI = upper respiratory tract infection

Drs. Kesten and Lanes are employees of Boehringer Ingelheim. Dr. Jara and Mr. Wentworth are consultants for Boehringer Ingelheim.

This study was supported by Boehringer Ingelheim Pharmaceuticals Inc. and Pfizer Inc.

Table Graphic Jump Location
Table 1. Characteristics of Pooled Clinical Trial Study Population (n = 7,819)*
* 

Data are presented as No. (%) or No. unless otherwise indicated.

Table Graphic Jump Location
Table 2. Selected Adverse Events From Pooled-Controlled Trials*
* 

Data are presented for two or more selected events in patients receiving tiotropium. NA = not applicable; LRTI = lower respiratory tract infection.

 

All rates are per 100 person-years.

Table Graphic Jump Location
Table 3. Serious, Including Fatal, Selected Adverse Events From Pooled Placebo-Controlled Trials*
* 

Data are presented for two or more selected events in patients receiving tiotropium. NA = not applicable.

 

All rates are per 100 person-years.

The authors thank Terry Keyser, Boehringer Ingelheim, Ridgefield, CT, for editorial support in preparation of this article.

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Figures

Tables

Table Graphic Jump Location
Table 1. Characteristics of Pooled Clinical Trial Study Population (n = 7,819)*
* 

Data are presented as No. (%) or No. unless otherwise indicated.

Table Graphic Jump Location
Table 2. Selected Adverse Events From Pooled-Controlled Trials*
* 

Data are presented for two or more selected events in patients receiving tiotropium. NA = not applicable; LRTI = lower respiratory tract infection.

 

All rates are per 100 person-years.

Table Graphic Jump Location
Table 3. Serious, Including Fatal, Selected Adverse Events From Pooled Placebo-Controlled Trials*
* 

Data are presented for two or more selected events in patients receiving tiotropium. NA = not applicable.

 

All rates are per 100 person-years.

References

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